ATM Signaling Facilitates Repair of DNA Double-Strand Breaks Associated with Heterochromatin

Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK.
Molecular cell (Impact Factor: 14.02). 07/2008; 31(2):167-77. DOI: 10.1016/j.molcel.2008.05.017
Source: PubMed


Ataxia Telangiectasia Mutated (ATM) signaling is essential for the repair of a subset of DNA double-strand breaks (DSBs); however, its precise role is unclear. Here, we show that < or =25% of DSBs require ATM signaling for repair, and this percentage correlates with increased chromatin but not damage complexity. Importantly, we demonstrate that heterochromatic DSBs are generally repaired more slowly than euchromatic DSBs, and ATM signaling is specifically required for DSB repair within heterochromatin. Significantly, knockdown of the transcriptional repressor KAP-1, an ATM substrate, or the heterochromatin-building factors HP1 or HDAC1/2 alleviates the requirement for ATM in DSB repair. We propose that ATM signaling temporarily perturbs heterochromatin via KAP-1, which is critical for DSB repair/processing within otherwise compacted/inflexible chromatin. In support of this, ATM signaling alters KAP-1 affinity for chromatin enriched for heterochromatic factors. These data suggest that the importance of ATM signaling for DSB repair increases as the heterochromatic component of a genome expands.

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    • "As HC is more compacted than EC, HC presents a barrier to the progression of NHEJ. Both ATM-deficient and KAP1 (an ATM substrate)-depleted cells showed delayed kinetics for γ-H2AX foci in HC regions following IR, and ATMdependent phosphorylation of KAP1 at serine 824 seemed to be related to this phenomenon (Goodarzi et al., 2008). "
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    ABSTRACT: The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to γ-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end-resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved.
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    • "ATM and DNA-PKcs are primarily activated in response to DSBs, whereas ATR functions as a major sensing factor in response to DNA replication stress (Cimprich and Cortez, 2008; Lovejoy and Cortez, 2009). ATM is immediately activated by DSB formation and contributes to the HR pathway by promoting chromatin remodeling and the DNA end resection required for subsequent strand exchange (Goodarzi et al., 2008; You et al., 2009), whereas DNA-PKcs senses DSBs as a complex with Ku proteins and promotes synapsis of two DNA ends and the subsequent end-joining reaction (DeFazio et al., 2002; Spagnolo et al., 2006). "
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    ABSTRACT: Camptothecin (CPT) inhibits DNA topoisomerase I (Top1) through a non-catalytic mechanism that stabilizes the Top1-DNA cleavage complex (Top1cc) and blocks the DNA re-ligation step, resulting in the accumulation in the genome of DNA single-strand breaks (SSBs), which are converted to secondary strand breaks when they collide with the DNA replication and RNA transcription machinery. DNA strand breaks mediated by replication, which have one DNA end, are distinct in repair from the DNA double-strand breaks (DSBs) that have two ends and are caused by ionizing radiation and other agents. In contrast to two-ended DSBs, such one-ended DSBs are preferentially repaired through the homologous recombination pathway. Conversely, the repair of one-ended DSBs by the non-homologous end-joining pathway is harmful for cells and leads to cell death. The choice of repair pathway has a crucial impact on cell fate and influences the efficacy of anticancer drugs such as CPT derivatives. In addition to replication-mediated one-ended DSBs, transcription also generates DNA strand breaks upon collision with the Top1cc. Some reports suggest that transcription-mediated DNA strand breaks correlate with neurodegenerative diseases. However, the details of the repair mechanisms of, and cellular responses to, transcription-mediated DNA strand breaks still remain unclear. In this review, combining our recent results and those of previous reports, we introduce and discuss the responses to CPT-induced DNA damage mediated by DNA replication and RNA transcription.
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    • "By contrast, repair of DSBs induced in heterochromatin is ATM dependent. At those DSBs, ATM would be required for chromatin remodeling permitting the loading and processing of repair machineries (Beucher et al., 2009; Goodarzi et al., 2008; Noon et al., 2010; Shibata et al., 2010). In addition, a recent report identified ATM as required for macroH2A1 loading and chromatin condensation, which are events shown to be necessary for BRCA1 retention at DSB and HR repair (Khurana et al., 2014). "

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